This research proposal is directed at investigating, on a fundamental level, the pathogenetic mechanism involved in injury to the enteric nervous system caused by diabetes mellitus. Specific experiments are designed to assess the factors controlling growth, differentiation and function of myenteric plexus neurons. the proposed research focuses on an extremely important area which is largely unexplored. The potential applicability to human health and disease is very large. The neuropathologic changes that occur in diabetic autonomic neuropathy have to been clearly established; little is known of he mechanisms involved in their evolution. In addition, little information is available relating pathologic changes to abnormal function. The lack of detailed information regarding the pathogenesis of diabetic enteric neuropathy has several causes: 1. The absence of reproducible and unequivocal neuropathologic changes in commonly used animal models, 2. an investigational focus on somatic nerves rather than the enteric nervous system, 3. the difficulty in studying enteric neurotransmitter in vivo, and, 4. the lack of appropriate in vitro models to explore neurocrine control mechanisms. These difficulties are reflected n the currently empiric, and often unsuccessful, treatment of human diabetic neuropathic disease. The proposed research concentrates on abnormalities of the enteric nervous system of the alimentary tract that are associated with diabetes mellitus. The proposed studies will focus on: 1. changes in neuron populations and enteric neurotransmitter levels caused by diabetes, and 2. elucidation of control mechanisms for neuronal growth differentiation and function that could b affected by diabetes. the proposed research addresses, at a fundamental level, the current deficiency of information about the pathogenesis of this important disease process.